Identification of natural antimicrobial peptides mimetic to inhibit Ca2+ influx DDX3X activity for blocking dengue viral infectivity.

ABSTRACT

Viruses are microscopic biological entities that can quickly invade and multiply in a living organism. Each year, over 36,000 people die and nearly 400 million are infected with the dengue virus (DENV). Despite dengue being an endemic disease, no targeted and effective antiviral peptide resource is available against the dengue species. Antiviral peptides (AVPs) have shown tremendous ability to fight against different viruses. Accelerating antiviral drug discovery is crucial, particularly for RNA viruses. DDX3X, a vital cell component, supports viral translation and interacts with TRPV4, regulating viral RNA metabolism and infectivity. Its diverse signaling pathway makes it a potential therapeutic target. Our study focuses on inhibiting viral RNA translation by blocking the activity of the target gene and the TRPV4-mediated Ca2+ cation channel. Six major proteins from camel milk were first extracted and split with the enzyme pepsin. The antiviral properties were then analyzed using online bioinformatics programs, including AVPpred, Meta-iAVP, AMPfun, and ENNAVIA. The stability of the complex was assessed using MD simulation, MM/GBSA, and principal component analysis. Cytotoxicity evaluations were conducted using COPid and ToxinPred. The top ten AVPs, determined by optimal scores, were selected and saved for docking studies with the GalaxyPepDock tools. Bioinformatics analyses revealed that the peptides had very short hydrogen bond distances (1.8 to 3.6 Å) near the active site of the target protein. Approximately 76% of the peptide residues were 5-11 amino acids long. Additionally, the identified peptide candidates exhibited desirable properties for potential therapeutic agents, including a net positive charge, moderate toxicity, hydrophilicity, and selectivity. In conclusion, this computational study provides promising insights for discovering peptide-based therapeutic agents against DENV.